We investigated the effects of rate of carbamazepine (CBZ) taper and CBZ level on seizure type and frequency in patients being withdrawn from antiepileptic drugs (AEDs). Rapid taper (4 days) led to significantly more generalized tonic-clonic seizures than slow taper (10 days). Neuropsychiatric disorders such as panic were increased during drug withdrawal. We have conducted several double-blind placebo-controlled trials of felbamate (FBM), an experimental antiepileptic drug (AED), in patients with complex partial seizures and the Lennox-Gastaut syndrome, a severe childhood epileptic encephalopathy. In the most recent study, we evaluated the effect of FBM monotherapy on seizure rate in patients undergoing presurgical monitoring. All their AEDs were withdrawn, and they were drug-free for 5+/-2.4 days before randomization to FBM or placebo. After a 4-day titration, seizures were counted for 14 days. Eight of 19 placebo patients randomized to placebo, compared to 13 of 21 on FBM, completed the 18-day study. Two FBM patients dropped out due to seizures, and 6 due to side effects, including anxiety, difficulty sleeping, abdominal discomfort, acute psychosis and orobuccal dyskinesia. Ten placebo patients met the criteria for premature termination due to seizures, and one had an episode of panic. Six of 11 placebo, and 4 of 8 FBM dropouts occurred during titration. Patients on FBM had significantly lower seizure rates, whether all randomized patients, patients who survived titration, or study completers were compared. Our trial design allowed us to collect information on both seizure reduction and drug toxicity more effectively than in conventional trials.